JP2749295B2 - High-molecular platinum complex compound, method for producing the same, and anticancer agent containing the same as an active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel high-molecular platinum complex compound derivative, a method for producing the same, and an anticancer agent.
For more information, see Polyphosphazene
The present invention relates to a controlled-release platinum complex compound derivative introduced into a compound, a method for producing the same, and an anticancer agent.

[0002]

2. Description of the Related Art Among anticancer drugs currently used, cisplatin, which is a derivative of a platinum series complex compound,
That is, cis- (NH ₃ ) ₂ PtCl ₂ was found to have an anticancer effect by B. Rosenberg, Nature 205 , 698 (1965) in the United States in 1965, and F.S.
It has been officially approved by the DA as an anticancer agent and is used as the most effective chemotherapeutic agent for various cancers such as testicular cancer, ovarian cancer, bladder cancer, and laryngeal cancer. However, strong toxicity (LD ₅₀ = 13 mg / kg, MJ Cleare, Biochimie
60 , 835 (1978)), and its use is currently restricted. On the other hand, carboplatin, which was approved by the FDA in 1989 and has recently started to be used as a second-generation anticancer drug, namely cis- (NH ₃ ) ₂ Pt (CBDC
A) (CBDCA = 1,1-cyclobutanedicarboxylate) is toxic (LD ₅₀ = 180 mg / kg, MJ Cleare, B
Although iochimie 60 , (1978)) is much lower than cisplatin, it is still not widely used because of its narrower and more expensive anticancer effects and the range of treatable cancers than cisplatin. Therefore, research for finding a third-generation anticancer drug having a superior anticancer effect and lower toxicity than cisplatin has been actively pursued worldwide, and this research report is too numerous to enumerate individually. However, commercialization has not reached a successful stage. The conditions under which the third-generation platinum complex compound should be prepared as an anticancer agent have excellent anticancer effect more than cisplatin, low toxicity as low as carboplatin,
Excellent effect on cisplatin or carboplatin-resistant cancer cells, no cross-resisitance,
The area of cancer cells that can be treated must be larger. In addition, the solubility of the drug in water is high,
Since various conditions must be satisfied, such as being chemically stable, candidate compounds currently undergoing clinical trials worldwide include:
There are about 10 types, but they have not been commercialized yet.

Although the anticancer activity and toxicity of cisplatin complex compounds have not yet been elucidated yet, the results of the studies so far can be briefly described as Pharmac. Ther. 25 , 297-326 (19)
84); as published in Chem. Rev. 87 , 1153-1181 (1987), when cisplatin is administered to the blood by injection or the like, a part of it undergoes hydrolysis, but blood chloride ion concentration Due to their high (〜100 mM), most exist as neutral molecules without ionization and diffuse through cell membranes. Since chloride concentration (4 mM) is low in cells, most chloride ions are removed by hydrolysis, and amine-platinum cations bind to DNA, which is a major component of cells, and interfere with DNA replication. Thus, a cell killing effect is exhibited. At this time, it is understood that the platinum complex compound cannot differentiate between normal cells and cancer cells, and thus exhibits cytotoxicity, and oligomers formed by hydrolysis of cisplatin also exhibit various toxicity in the body. However, the specific relationship between the molecular structure of the amine neutral ligand and the anion in the cisplatin molecule on anticancer activity and internal toxicity has not yet been elucidated.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have intensively studied to develop a new third-generation platinum-series anticancer drug which has better anticancer effect than existing cisplatin and has low toxicity. As a result, after introducing a group imparting solubility and an aminodicarboxylic acid derivative to a polyphosphazene-based polymer chain that is a biodegradable inorganic polymer, the cisplatin-based platinum complex compound is bonded to the aminodicarboxylic acid via hydrolysis. The high molecular weight platinum complex compound of the following general formula (I) produced by the above method has a much better anticancer effect than cisplatin, and its toxicity is as low as carboplatin, especially against cisplatin-resistant cancer cells. Not only has excellent cancer effect, but also has excellent anticancer effect against lung, stomach and intestinal cancer cells that are difficult to treat with existing cisplatin It was. This is because when the drug of the present invention in which a platinum series anticancer drug is introduced into the polymer chain is administered into the body,
It is considered that the active ingredient of the platinum complex compound is controlled and released from the polymer chain, and the appropriate effective concentration of the drug is maintained for a certain period of time, thereby exhibiting low toxicity and excellent anticancer effect.

The present invention provides a compound represented by the following general formula (I):
The present invention relates to a novel polymer platinum complex compound derivative introduced into polyphosphazene, which has an excellent anticancer effect, and a method for producing the same.

[0006]

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Wherein the polymer skeleton is based on a polyphosphazene having P = N repeating units, and S is a group imparting solubility and is a hydroxyl group or methoxy, ethoxy, (2-methoxy A) represents an alkoxy group such as ethoxy, or an alkylamino group such as methylamino, dimethylamino; A is a monodentate neutral ligand ammonia, or has 1 to 3 carbon atoms such as methylamine, ethylamine Alkylamine or cyclopropylamine (CP
A) or ethylenediamine (en), propylenediamine (pn), 2-hydroxy-1,3-
Diaminopropane (HDAP), 2,2-dimethyl-
1,3-diaminopropane (DMDAP), 1,1-diaminomethylcyclobutane (DAMCB), tetrahydro-4H-pyran-4,4-dimethanamine (THPD)
MA), AA type chelate obtained by combining two amines selected from 2,2-bisaminomethyl-1,3-propanediol (BAMPDO) and trans-1,2-diaminocyclohexane (DACH) X represents an integer 0, 1 or 2 and the anionic portion of the aminodicarboxylic acid, depending on the type of aminodicarboxylic acid,
When x = 0, aminomalonic acid (Am) derivative, x = 1
Represents an aspartic acid (Asp) derivative, x = 2 represents a glutamic acid (Glt) derivative; M represents a sodium ion (Na ⁺ ), a potassium ion (K
⁺ ) Indicates two alkali metal ions or two ammonium ions such as calcium ion (C
a ²⁺ ), one alkaline earth metal ion such as barium ion (Ba ²⁺ ); m value indicating the content of the platinum complex is 0.2 to 1,
The n value indicating the degree of polymerization of polyphosphazene is 10 to 1
00. ]

The high molecular weight platinum complex compound of the formula (I) wherein the platinum complex compound is introduced into the polyphosphazene chain according to the present invention is a novel substance and has excellent anticancer effect and excellent properties. It was recognized that.

According to the present invention, there is provided a process for producing a platinum complex compound derivative introduced into a polyphosphazene of the general formula (I),
This will be briefly described below.

That is, polydichlorophosphazene has
After introducing an aminodicarboxylic acid derivative as a platinum complex compound linking agent and a group for imparting solubility, a hydrolysis step is carried out, and then an ammonium salt or an alkali metal salt of the general formula (II) or an alkaline earth of the general formula (III) A metal salt is obtained, and the compound of the general formula (II) or (III) is reacted with the diamine platinum acid salt of the general formula (IV) in a molar ratio of 1: 0.2 to 1 in an aqueous solution at room temperature. By doing so, a polymer platinum complex compound of the general formula (I) is obtained.

[0011]

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[Where S, A, x, M, m and n
Is as defined above, M (I) represents an ammonium ion or an alkali metal ion, and M (I
I) represents an alkaline earth metal ion, X ₂ is an anion, and is composed of two NO ₃ ⁻ ions or one SO ₄
^{Shows 2-} ions. ]

The amine-platinum water-soluble acid salt of the general formula (IV) can be obtained from the amine platinum iodine of the general formula (V) and a water-soluble acid salt of silver in the literature (RC Harrison, Inorg. Chimica Acta 46 ,
L15 (1980)).

[0014]

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In the general formula (V), A is as defined in the general formula (I). The amine platinum iodine of the general formula (V) can be obtained by combining potassium tetrachloride, potassium iodide, and an amine compound with the reference (MJ Cleare, Biochimie 6).
0 , 835 (1978)).

The method for producing the polymer platinum complex compound derivative represented by the general formula (I) of the present invention will be specifically described. First, a polyphosphazene, which is a polymer skeleton for introducing a platinum complex compound, is synthesized, a group imparting solubility to the polymer skeleton and a platinum complex compound linking agent are introduced, and finally, a platinum complex compound is introduced. It can be divided into stages.

First, polyphosphazene is synthesized by a conventional method (eg, Macromolecule, 8 , 36 (1975)), which is obtained by thermally polymerizing a phosphazene trimer, ie, (N = PCl ₂ ) ₃ , to obtain a polydichlorophosphazene linear polymer. , That is, (N = P
Cl ₂ ) _n . The polymer is dissolved in anhydrous benzene, toluene, tetrahydrofuran or dioxane solvent with excess triethylamine as a hydrogen chloride scavenger. This solution is prepared by combining aminomalonic acid, aspartic acid or glutamic acid methyl ester, ethyl ester, benzyl ester or alkylamide, which is an amino acid having two carboxyl groups, as a platinum complex compound linking agent with the unit molecule of the phosphazene polymer. After gradually adding to the solution dissolved in the solvent in the same molar ratio, the mixture is stirred at room temperature for 5 to 10 hours. After filtering the precipitated triethylamine hydrochloride, the filtrate is water or a water-soluble alcohol such as methanol, ethanol, or methoxyethanol as a reagent for introducing a group imparting solubility,
Alternatively, after adding triethylamine in an equivalent molar ratio together with a water-soluble amine such as methylamine or ethylamine, the mixture is again stirred at room temperature for 2 to 10 hours, and refluxed if necessary.
When the thus obtained reaction product containing a polymer in which both the amino acid and the group imparting solubility are substituted is poured into an excessive amount of n-hexane, most of the polymer precipitates. A purification process in which the precipitated polymer obtained by filtering the hexane solution is redissolved in a polar solvent such as tetrahydrofuran or dioxane and then poured into distilled water to precipitate the polymer is repeated two to three times.
The polymer thus purified is redissolved in a co-solvent of alcohol-tetrahydrofuran, and the solution is added with 1.0 to 1.5 equivalents of an alkali metal such as sodium or potassium based on the substituted amino acid. Or a hydroxide of an alkaline earth metal such as calcium or barium, and then hydrolyzing by stirring at room temperature for 2 to 10 hours to obtain the aqueous solution of the general formula (II) or the general formula (III). Precipitate the amino acid metal salt. This precipitate is filtered, washed thoroughly with alcohol or acetone, and dried,
The reaction with the amine platinum complex intermediate is carried out as follows.

That is, an excess amount of potassium iodide is reacted with an aqueous solution of potassium platinum tetrachloride, and then reacted with 2 equivalents of a desired amine (A) in an aqueous solution to obtain an amine platinum iodine intermediate of the general formula (V). After obtaining the product by the method described in the literature, a water-soluble acid salt of silver, that is, the same equivalent of silver nitrate or silver sulfate is added thereto, and the mixture is stirred at room temperature for 2 to 10 hours to precipitate silver iodide. A water-soluble amine platinum acid salt of IV) is obtained. The aqueous solution of the amine platinum acid salt thus obtained and the aqueous solution of the amino acid alkali metal salt of polyphosphazene of the general formula (II) or the alkaline earth metal salt of the general formula (III) obtained above were mixed with 0.2 to 1: By stirring in an aqueous solution at a molar ratio of 1 to obtain a compound of the general formula (I)
Is formed, and a nitrate or a sulfate of an alkali metal or an alkaline earth metal is produced as a by-product. The nitrate or sulfate thus obtained as a by-product can be obtained by placing the reaction solution in a container made of a semipermeable membrane (passing a molecular weight of 1,000 or less) and dialyzing with distilled water for 10 to 24 hours, or polyphosphazene in the reaction solution. Separation and purification can be performed using the difference in solubility between the platinum complex compound and the by-product nitrate or sulfate. For example, when reacting an amino acid alkaline earth metal salt of polyphosphazene with an amine platinum sulfate, the alkaline earth metal sulfate is hardly soluble in water, so that it precipitates, and only the polyphosphazene amino acid platinum complex compound is soluble in water. So
This may be separated by filtration. When reacting an amino acid alkali metal salt of polyphosphazene with a nitrate of amine platinum, potassium nitrate or sodium nitrate is produced as a by-product, but since these have high solubility in water, the amino acid platinum complex compound of polyphosphazene is contained in the reaction solution. Coexist with However, sodium nitrate and potassium nitrate are soluble in alcohol, and platinum complex compounds are almost insoluble.
Separation can be achieved using a water / alcohol solvent. Further, when reacting the amino acid sodium or potassium salt of polyphosphazene with the amine platinum sulfate, since sodium sulfate or potassium sulfate as a by-product is water-soluble,
If a water / acetone solvent is used, separation and purification can be easily performed. The production method of the general formula (I) is represented by the following reaction formula.

[0019]

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[0020]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 ΔNP (OH) [Asp.Pt (DACH)] _0.9 (As
p · K ₂ ) Synthesis of _0.1 · 2H ₂ O｝ _n Hexachlorocyclotriphosphazene [(N = PCl
₂ ) ₃ ] 3.0 g (8.63 mmol) of anhydrous aluminum chloride and 0.30 g (2.25 mmol) of anhydrous aluminum chloride were placed in a 220 mm × 23 mm Pyrex ampule, sealed, and reacted at 250 ° C. for 2 hours while rotating at 1 rpm. And polydichlorophosphazene. After cooling the ampoule at room temperature, it was opened in a dry box under a stream of argon and the product was
It was dissolved in purified anhydrous THF, and the solution was used for the substitution reaction as it was. 13.2 g (27.2 mmol) of L-aspartoyl dibenzyl ester-p-toluenesulfonate was added to THF.
6. Add 400 ml, cool to 0 ° C., and triethylamine
56 ml (54.4 mmol) was added and stirred for 30 minutes. To this, 150 ml of a THF solution in which 3.0 g of the previously synthesized polydichlorophosphazene was dissolved was added dropwise over 1 hour, followed by stirring at room temperature for 20 hours. Precipitate formed at this time to (Et ₃ N · HCl and triethylammonium -p- toluenesulfonate) filtrate was filtered, triethylamine 3.78 ml (27.2 mmol) and water 0.49 ml (27.2 mmol) And stirred at room temperature for 12 hours. At this time, the precipitate (Et ₃ N ·
HCl) was filtered, the filtrate was distilled under reduced pressure at 30 ° C., and the product obtained was again dissolved in THF and then dropped into an excessive amount of n-hexane to obtain a white precipitate. Was dissolved in THF and then added dropwise to an excess amount of distilled water to obtain a white polymer [NP (OH) (L-Asp. (CH ₂ P)
h) ₂ )] _n was dried under reduced pressure (yield: 85%).

THF-MeOH in which 4.0 g (10.7 mmol) of the polyphosphazene derivative thus synthesized was dissolved
(1: 1, vol.%) 1.80 KOH was added to 80 ml of the mixed solution.
g (32.1 mmol) or 1.28 g of NaOH (32.1 mmol
50 ml of a mixed solution of l) in THF-MeOH (1: 1, vol.%) was gradually added. The precipitate formed after stirring for 5 hours was filtered and washed with a sufficient amount of a THF-MeOH mixed solution and ethyl ether. After dissolving the precipitate in 40 ml of 2N KOH or 2N aqueous NaOH, 500 ml of T
The mixture was dropped into a mixed solution of HF-MeOH (1: 1, vol.%) And recrystallized, and the resulting precipitate [NP (OH) (L-Asp
.K ₂ )] _n or [NP (OH) (Asp.Na ₂ )] _n
Was filtered, washed with methanol and ethyl ether, and dried (yield: 90%).

On the other hand, the platinum intermediate (DACH) Pt
2.08 g (3.70 mmol) of I ₂ and 1.15 of Ag ₂ SO ₄
After reacting g (3.70 mmol), AgI was filtered and removed, and 100 ml of a (DACH) PtSO ₄ aqueous solution obtained above was synthesized [NP (OH) (L-Asp · K ₂ )] _n
1.0 g (3.70 mmol) of a dissolved aqueous solution (30 ml) was added, and the mixture was stirred for 1 hour in the absence of light. The reaction mixture was concentrated under reduced pressure to 30 ml to remove the K ₂ SO ₄ dissolved in the reaction mixture solution. 400 ml of acetone here
Was added, and the resulting precipitate was washed with ethyl ether and dried under reduced pressure to obtain a final polymer platinum complex compound.

Elemental analysis (%): C, 22.3; H, 4.27; N, 9.58; P, 5.
25; Pt, 34.3 Theoretical value (%): C, 21.6; H, 4.50; N, 10.1; P, 5.
58; Pt, 35.2 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.2-1.3 (4H),
1.6 (2H), 2.1 (2H), 2.4 (2H), 2.7 (2H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 516 (m), 714 (m),
816 (m), 1034 (m), 1065 (m), 1172 (m), 1248 (m), 1384
(s), 1450 (m), 1618 (s), 3213 (s), 3428 (s)

Example 2 ΔNP (OH) [Asp · Pt (DACH)] _0.5 (As
p · K ₂ ) Synthesis of _0.5 · 3H ₂ O｝ _n (DACH) PtI ₂ 1.04 g (1.85 mmol), Ag
0.58 g (1.85 mmol) of ₂ SO ₄ and [NP (OH)
(Asp · K ₂ )] _n 1.0 g (3.70 mmol) in Example 1
The reaction was carried out in the same manner as in the above to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 18.5; H, 3.31; N, 5.86; P, 6.
56; Pt, 21.4 Theoretical (%): C, 19.1; H, 3.87; N, 6.37; P, 7.
05; Pt, 22.2 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.2-1.3 (4H),
1.6 (2H), 2.1 (2H), 2.4 (2H), 2.7 (2H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ):
518 (m), 614 (m), 1065 (m),
1119 (s), 1167 (m), 1307
(M), 1393 (s), 1591 (s), 16
45 (m), 2934 (m), 3213 (s),
3406 (s)

Example 3 @NP (OH) [Asp.Pt (DACH)]
Synthesis of _0.2 (Asp · K ₂ ) _0.8 · 3H ₂ O｝ _n (DACH) 0.42 g (0.74 mmol) of PtI ₂ , Ag
0.23 g (0.74 mmol) of ₂ SO ₄ and [NP (OH)
(Asp · K ₂ )] _n 1.0 g (3.70 mmol) in Example 1
The reaction was carried out in the same manner as in the above to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 15.9; H, 3.14; N, 8.25; P, 7.
38; Pt, 9.77 Theoretical (%): C, 16.9; H, 3.76; N, 9.08; P, 8.
36; Pt, 10.54 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.2-1.3 (4H),
1.6 (2H), 2.1 (2H), 2.4 (2H), 2.7 (2H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 534 (m), 620 (m),
979 (m), 1060 (m), 1124 (s), 1205 (m), 1307 (m), 1404
(s), 1591 (s), 2945 (m), 3224 (s), 3406 (s)

Example 4 ΔNP (OH) [Asp · Pt (CPA) ₂ ] _0.9 (As
p · K ₂ ) _0.1 · 2H ₂ O｝ _n Synthesis of (CPA) ₂ PtI ₂ 2.08 g (3.70 mmol), Ag ₂
1.15 g (3.70 mmol) of SO ₄ and [NP (OH)
(Asp · K ₂ )] _n 1.0 g (3.70 mmol) in Example 1
The reaction was carried out in the same manner as in the above to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 21.7; H, 3.82; N, 9.33; P, 5.
18; Pt, 34.7 Theoretical (%): C, 21.9; H, 4.23; N, 10.35; P,
6.02; Pt, 34.1 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 0.7 (8H), 2.5 (2
H), 3.7 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 619 (m), 827 (m),
964 (m), 1030 (m), 1122 (m), 1261 (m), 1375 (s), 1637
(s), 3103 (m), 3188 (s), 3404 (m)

Example 5 ΔNP (OH) [Asp.Pt (NH ₃ ) ₂ ] .3H ₂ O
Synthesis of｝ _n 1.79 g (3.70 mmol) of (NH ₃ ) ₂ PtI ₂ , Ag ₂
1.15 g (3.70 mmol) of SO ₄ and [NP (OH)
(L-Asp.K ₂ )] _n (1.0 g, 3.70 mmol) was reacted in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 10.4; H, 2.88; N, 9.54; P, 5.
98; Pt, 40.4 Theoretical (%): C, 10.1; H, 3.37; N, 8.84; P, 6.
52; Pt, 41.1 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 2.7 (2H), 3.9 (1
H) Infrared spectrum (KBr cell, cm ^-1 ): 619 (m), 1118 (m),
1369 (m), 1639 (s), 3128 (m), 3259 (s), 3443 (m)

Example 6 ΔNP (OH) [Asp · Pt (en)] _0.85 (Asp
· K ₂₎ of _0.15 · 2H ₂ O} _n Synthesis _{(en) PtI 2 1.88g (3.70mmol} ), Ag 2 S
1.15 g (3.70 mmol) of O ₄ and [NP (OH) (L
-Asp.K ₂ )] _{n in} Example 1 (1.0 g, 3.70 mmol).
The reaction was carried out in the same manner as in the above to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 15.8; H, 4.54; N, 10.7; P, 6.
11; Pt, 36.4 Theoretical value (%): C, 15.0; H, 3.55; N, 11.4; P, 6.
78; Pt, 36.3 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 2.4-2.6 (6H),
3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 570 (m), 765 (m),
1049 (m), 1128 (m), 1291 (m), 1400 (s), 1638 (s), 3267
(m), 3450 (m)

Example 7 ΔNP (OH) [Asp · Pt (pn)] _0.85 (Asp
・ K ₂ ) Synthesis of _0.15 · 2H ₂ O｝ _n (pn) 1.94 g (3.70 mmol) of PtI ₂ , Ag ₂ S
1.15 g (3.70 mmol) of O ₄ and [NP (OH) (L
-Asp · K ₂ )] _{n in an amount of} 1.0 g (3.70 mmol) in Example 1.
The reaction was carried out in the same manner as in the above to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 16.5; H, 4.43; N, 10.7; P, 6.
14; Pt, 35.4 Theoretical value (%): C, 16.7; H, 3.81; N, 11.0; P, 6.
58; Pt, 35.2 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.4 (2H), 2.4-
2.7 (6H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ):
530 (m), 936 (m), 1108 (m),
1196 (m), 1291 (m), 1402
(S), 1634 (s), 2932 (m), 32
24 (m), 3428 (m)

Example 8 @NP (OH) [Asp.Pt (NH ₂ CH ₃ )
₂ ] _0.85 (Asp · K ₂ ) _0.15 · 2H ₂ O｝ _n Synthesis of (CH ₃ NH ₂ ) ₂ PtI ₂ 1.89 g (3.70 mmol),
1.15 g (3.70 mmol) of Ag ₂ SO ₄ and [NP (O
H) (L-Asp · K ₂ )] _n (1.0 g, 3.70 mmol) was reacted in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 15.1; H, 4.58; N, 10.8; P, 6.
36; Pt, 36.5 Theoretical (%): C, 14.9; H, 3.91; N, 11.3; P, 6.
76; Pt, 36.2 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 2.4-2.7 (8H),
3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 582 (m), 753 (m),
1084 (m), 1237 (m), 1418 (s), 1621 (s), 2923 (m), 3218
(m), 3421 (m)

Example 9 ｛NP (OH) [Asp.Pt (NH ₂ C ₂ H ₅ ) ₂ ]
Synthesis of _0.8 (Asp · K ₂ ) _0.2 · 2H ₂ O｝ _n (NH ₂ C ₂ H ₅ ) ₂ PtI ₂ 1.99 g (3.70 mmol)
l), 1.15 g (3.70 mmol) of Ag ₂ SO ₄ and [N
P (OH) (L-Asp.K ₂ )] _n 1.0 g (3.70 mm
ol) was reacted in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 18.3; H, 4.32; N, 10.8; P, 6.
20; Pt, 33.6 Theoretical value (%): C, 18.3; H, 4.40; N, 10.7; P, 6.
56; Pt, 33.1 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.1 (6H), 2.5-
2.8 (6H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 603 (m), 762 (m),
1064 (m), 1201 (m), 1231 (m), 1407 (s), 1633 (s), 2934
(m), 3214 (s), 3402 (s)

Example 10 NP (OH) [Asp.Pt (HDAP)]
Synthesis of _0.8 (Asp · K ₂ ) _0.2 · 2H ₂ O｝ _n (HDAP) 1.99 g (3.70 mmol) of PtI ₂ , Ag
1.15 g (3.70 mmol) of ₂ SO ₄ and [NP (OH)
(L-Asp.K ₂ )] _n (1.0 g, 3.70 mmol) was reacted in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 15.9; H, 4.4
2; N, 10.2; P, 6.13; Pt,
33.1 Theoretical value (%): C, 16.3; H, 3.2
0; N, 10.7; P, 6.56; Pt,
33.1 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 2.3-2.5 (6H),
3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 532 (m), 851 (m),
974 (m), 1071 (m), 1189 (m), 1312 (m), 1402 (s), 1632
(s), 3202 (m), 3449 (m)

Example 11 ΔNP (OH) [Asp · Pt (DMDAP)]
Synthesis of _0.8 (Asp · K ₂ ) _0.2 · 2H ₂ O｝ _n (DMDAP) 2.04 g (3.70 mmol) of PtI ₂ , A
g ₂ SO ₄ 1.15 g (3.70 mmol) and [NP (O
H) (L-Asp · K ₂ )] _n (1.0 g, 3.70 mmol) was reacted in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 21.4; H, 5.26; N, 9.52; P, 6.
23; Pt, 32.8 Theoretical (%): C, 20.0; H, 4.31; N, 10.5; P, 6.
43; Pt, 32.4 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.4 (6H), 2.3-
2.5 (6H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 522 (m), 700 (m),
915 (m), 1108 (m), 1200 (m), 1221 (m), 1307 (m), 1400
(m), 1632 (s), 2945 (m), 3224 (s), 3442 (s)

Example 12 ΔNP (OH) [Asp · Pt (DAMCB)]
Synthesis of _0.8 (Asp · K ₂ ) _0.2 · 2H ₂ O｝ _n (DAMCB) 2.08 g (3.70 mmol) of PtI ₂ , A
g ₂ SO ₄ 1.15 g (3.70 mmol) and [NP (O
H) (L-Asp · K ₂ )] _n (1.0 g, 3.70 mmol) was reacted in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 22.1; H, 4.51; N, 9.84; P, 5.
87; Pt, 32.1 Theoretical value (%): C, 21.5; H, 4.23; N, 10.3; P, 6.
31; Pt, 31.8 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 0.8-1.1 (6H),
2.2-2.4 (6H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 530 (m), 920 (m),
1087 (m), 1114 (m), 1200 (m), 1400 (s), 1632 (s), 2966
(m), 3224 (m), 3442 (m)

Example 13 ΔNP (OCH ₃ ) [Asp · Pt (DACH)]
Synthesis of _0.8 (Asp · K ₂ ) _0.2 · 2H ₂ O｝ _n 13.2 g (27.2 mmol) of L-aspartyl dibenzyl ester-p-toluenesulfonate was added to THF 400
and cooled at 0 ° C. to 7.56 ml of triethylamine.
(54.4 mmol) and stirred for 30 minutes. 150 ml of a THF solution in which 3.0 g of the polydichlorophosphazene synthesized in Example 1 was dissolved was added dropwise over 1 hour, and the mixture was stirred at room temperature for 20 hours. The precipitate (E
After filtration of t ₃ N · HCl and triethylammonium-p-toluenesulfonate), the filtrate was concentrated to 30 ml at 30 ° C. or lower, and 50 ml of methanol and 3.78 ml (27.7 mmol) of triethylamine were added thereto. 60-7
Stirred at 0 ° C. for 14 hours. The precipitate (Et ₃ N · HCl) generated at this time was filtered, and then the solvent of the filtrate was evaporated at 30 ° C. or lower, and the obtained product was dissolved in THF.
A white precipitate was obtained by dropwise addition to excess n-hexane. This precipitate was dissolved again in THF and dropped into an excessive amount of distilled water to obtain only a white polymer by precipitation. After repeating this step twice, the obtained polymer [NP (OCH ₃ ) (L
The _{-Asp · (CH 2 Ph) 2} ) ] _n and dried under reduced pressure. 4.0 g of the polyphosphazene derivative synthesized in this manner (1
[NP (OCH ₃ ) (L-Asp · K ₂ )] _n (1.0 g, 0.7 mmol).
52 mmol) and 1.98 g of (DACH) PtI ₂ (3.5
2 mmol) and 1.10 g (3.52 mmol) of AgSO ₄ were reacted in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 23.4; H, 4.45; N, 9.67; P, 5.
88; Pt, 31.8 Theoretical (%): C, 23.3; H, 4.51; N, 9.98; P, 6.
13; Pt, 30.9 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.2-1.3 (4H),
1.6 (2H), 2.2 (2H), 2.5 (2H), 2.7 (2H), 3.4 (3H), 3.8 (1
H) Infrared spectrum (KBr cell, cm ^-1 ): 516 (m), 613 (m),
1110 (m), 1034 (m), 1172 (m), 1253 (m), 1398 (s), 1594
(s), 2940 (m), 3218 (s), 3246 (m)

Example 14 ΔNP (OCH ₃ ) [Asp.Pt (NH ₃ ) ₂ ]
Synthesis of _0.85 (Asp · K ₂ ) _0.15 · 2H ₂ O｝ _n (NH ₃ ) ₂ PtI ₂ 1.78 g (3.52 mmol), Ag ₂
1.10 g (3.52 mmol) of SO ₄ and [NP (OCH ₃ )
(Asp · K ₂ )] _n 1.0 g (3.52 mmol) in Example 1
Reaction was carried out in the same manner as in Example 3 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 13.1; H, 4.33; N, 11.0; P, 7.
42; Pt, 37.1 Theoretical value (%): C, 13.5; H, 3.64; N, 11.6; P, 6.
94; Pt, 37.2 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 2.5 (2H), 3.3 (3
H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 520 (m), 714 (m),
1038 (m), 1174 (m), 1205 (m), 1377 (s), 1624 (s), 2927
(m), 3267 (s), 3442 (m)

Example 15 ΔNP (OC ₂ H ₅ ) [Asp · Pt (DACH)]
_0.8 (Asp · K ₂ ) _0.2 · 2H ₂ O｝ _n Synthesis 3.0 g of polydichlorophosphazene, L-aspartoyldibenzyl ester-p-toluenesulfonate 1
3.2 g (27.2 mmol) and ethanol (50ml) was prepared by reacting _{[NP (OC 2 H 5) (} L-Asp · K 2) ]
_n 1.0 g (3.34 mmol) and (DACH) PtI ₂
1.88 g (3.34 mmol) and 1.04 g of Ag ₂ SO ₄
(3.34 mmol) was reacted in the same manner as in Example 13 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 28.7; H, 5.10; N, 9.01; P, 5.
58; Pt, 29.1 Theoretical (%): C, 28.6; H, 4.69; N, 9.69; P, 5.
95; Pt, 30.0 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.1-1.3 (4H),
1.4-1.6 (6H), 2.2 (2H), 2.4 (2H), 2.8 (2H), 3.4 (2H), 3.
8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 516 (m), 614 (m),
963 (m), 1032 (m), 1122 (m), 1173 (m), 1248 (m), 1302
(m), 1390 (s), 1624 (s), 2923 (m), 3212 (s), 3426 (s)

Example 16 ΔNP (OC ₂ H ₅ ) [Asp · Pt (NH ₃ ) ₂ ]
Synthesis of _0.85 (Asp · K ₂ ) _0.15 · 2H ₂ O｝ _n 1.61 g (3.34 mmol) of (NH ₃ ) ₂ PtI ₂ , Ag ₂
1.04 g (3.34 mmol) of SO ₄ and [NP (OC ₂ H
₅ ) (Asp · K ₂ )] _n (1.0 g, 3.34 mmol) was reacted in the same manner as in Example 13 to obtain a polymer platinum complex compound.

Elemental analysis value (%): C, 19.8; H, 4.4
6; N, 10.9; P, 6.01; Pt,
35.8 Theoretical value (%): C, 20.1; H, 3.9
6; N, 11.2; P, 6.72; Pt,
36.0 hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.3 (3H), 2.6 (2
H), 3.3 (2H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 601 (m), 889 (m),
1043 (m), 1218 (m), 1382 (s), 1630 (s), 2936 (m), 3213
(s), 3426 (s)

Example 17 ΔNP (OC ₂ H ₄ OCH ₃ ) [Asp · Pt (DAC
H)] _0.8 (Asp · K ₂ ) _0.2 · 2H ₂ O｝ _n Synthesis of 3.0 g of polydichlorophosphazene, L-aspartoyldibenzyl ester-p-toluenesulfonate 1
3.2 g (27.2 mmol) and CH ₃ OCH ₂ CH ₂ ON
a. obtained by reacting 2.70 g (27.2 mmol) of a
(OCH ₂ CH ₂ OCH ₃ ) (L-Asp · K ₂ )] _n 1.
0 g (3.04 mmol) and (DACH) PtI ₂ 1.71
g (3.04 mmol) and 0.95 g of Ag ₂ SO ₄ (3.04
mmol) was reacted in the same manner as in Example 13 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 25.7; H, 5.38; N, 8.76; P, 5.
10; Pt, 28.9 Theoretical (%): C, 25.8; H, 4.81; N, 9.18; P, 5.
64; Pt, 28.4 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.2-1.4 (6H),
1.6 (2H), 2.1 (2H), 2.4 (2H), 2.7 (2H), 3.2-3.4 (5H),
3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 516 (m), 840 (m),
969 (m), 1044 (m), 1124 (m), 1162 (m), 1205 (m), 1253
(m), 1398 (s), 1624 (m), 2940 (m), 3234 (s), 3440 (s)

Example 18 ｛NP (NHCH ₃ ) [Asp · Pt (DACH)]
Synthesis of _0.8 (Asp · K ₂ ) _0.2 · 2H ₂ O｝ _n 13.2 g (27.2 mmol) of L-aspartyl dibenzyl ester-p-toluenesulfonate was added to THF 400
and cooled at 0 ° C. to 7.56 ml of triethylamine.
(54.4 mmol) and stirred for 30 minutes. A solution of 3.0 g of polydichlorophosphazene synthesized in Example 1 in 150 ml of THF was added dropwise over 1 hour, and the mixture was stirred at room temperature for 20 hours. Precipitate formed at this time (Et ₃ N · HCl and triethylammonium -
After filtration of (p-toluenesulfonate), the filtrate was concentrated to 0%.
After cooling at 0 ° C. and adding 54.4 mmol of methylamine (liquefied with a dry ice-acetone mixed refrigerant), the mixture was stirred for 10 hours. After removing the solvent of the reaction product and dissolving the obtained product in 50 ml of methanol, the solution was dialyzed for 48 hours using a dialysis membrane (molecular weight cutoff: 1,000), and the solution was concentrated to 30 ml. The mixture was added dropwise to a quantity of acetone to obtain only a white polymer as a precipitate. 4.0 g (9.89 mmol) of the polyphosphazene derivative synthesized above was hydrolyzed as in Example 1 to obtain [NP (NHCH ₃ )].
(L-Asp · K ₂ )] _n (1.0 g, 3.70 mmol);
(DACH) 2.08 g (3.70 mmol) of PtI ₂ and A
1.15 g (3.70 mmol) of g ₂ SO ₄ was reacted in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 24.8; H, 4.62; N, 12.4; P, 5.
92; Pt, 30.8 Theoretical value (%): C, 24.3; H, 4.64; N, 12.8; P, 6.
14; Pt, 31.0 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.2-1.4 (4H),
1.6 (2H), 2.1 (2H), 2.4-2.6 (7H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 518 (m), 614 (m),
716 (m), 904 (m), 1060 (m), 1114 (m), 1248 (m), 1307
(m), 1162 (m), 1387 (s), 1586 (s), 1645 (s), 2923 (m),
3245 (s), 3385 (s)

Example 19 ΔNP (NHCH ₃ ) [Asp · Pt (NH ₃ ) ₂ ]
Synthesis of _0.85 (Asp · K ₂ ) _0.15 · 2H ₂ O｝ _n (NH ₃ ) ₂ PtI ₂ 1.79 g (3.70 mmol), Ag ₂
1.15 g (3.70 mmol) of SO ₄ and [NP (NHCH
₃ ) (L-Asp · K ₂ )] _n (1.0 g, 3.70 mmol) was reacted in the same manner as in Example 18 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 13.3; H, 4.28; N, 14.7; P, 6.
89; Pt, 37.4 Theoretical value (%): C, 13.5; H, 3.87; N, 14.8; P, 6.
96; Pt, 37.3 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 2.5 (3H), 2.7 (2
H), 3.9 (1H) Infrared spectrum (KBr cell, cm ^-1 ):
518 (m), 963 (m), 1114 (m),
1162 (m), 1231 (m), 1253
(M), 1302 (m), 1401 (s), 16
39 (s), 2945 (m), 3245 (s),
3421 (s)

Example 20 @NP (N (CH ₃ ) ₂ )
[Asp · Pt (DACH)] _0.8 (Asp · K ₂ ) _0.2 · 2H ₂ O｝ _n Synthesis of polydichlorophosphazene 3.0 g, L-aspartoyldibenzyl ester-p-toluenesulfonate 1
It was obtained by reacting 3.2 g (27.2 mmol) with 2.22 g (27.2 mmol) of dimethylamine hydrochloride [NP
(N (CH ₃ ) ₂ ) (L-Asp · K ₂ )] _n 1.0 g (3.3
6 mmol) and 1.89 g (3.36) of (DACH) PtI _2.
mmol) and 1.05 g (3.36 mmol) of Ag ₂ SO ₄ were reacted in the same manner as in Example 18 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 23.6; H, 4.98; N, 11.9; P, 5.
83; Pt, 30.7 Theoretical value (%): C, 23.6; H, 4.90; N, 12.4; P, 5.
98; Pt, 30.1 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.1-1.3 (4H),
1.5 (2H), 2.1 (2H), 2.3-2.5 (8H), 3.9 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 502 (m), 625 (m),
985 (m), 1065 (m), 1151 (m), 1237 (m), 1291 (m), 1392
(s), 1632 (s), 2923 (m), 3191 (s), 3442 (s)

Example 21 ΔNP (OH) [Glt · Pt (DACH)]
Synthesis of _0.9 (Glt · K ₂ ) _0.1 · 2H ₂ O｝ _n 3.0 g of polydichlorophosphazene, L-glutamoyl dibenzyl ester-p-toluenesulfonate 13.
6 g (27.2 mmol), 7.57 ml of triethylamine (5
4.4 mmol) and H ₂ O 0.49ml (27.2mmol)
[NP (OH) (L-Glt · K ₂ )]
_n (1.0 g, 3.52 mmol) and (DACH) PtI ₂
1.98 g (3.52 mmol) and 1.10 g of Ag ₂ SO ₄
(3.52 mmol) was reacted in the same manner as in Example 1 to obtain a reaction mixture containing a high-molecular platinum complex, which was dialyzed for 15 hours using a semipermeable membrane (molecular weight cutoff: 1,000). By-product K ₂ SO ₄ was removed. This purified solution was freeze-dried under reduced pressure to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 23.6; H, 4.21; N, 9.59; P, 6.
08; Pt, 34.0 theoretical (%): C, 23.6; H, 4.5
0; N, 10.1; P, 5.86; Pt,
33.2 Hydrogen nuclear magnetic resonance spectrum _(D 2 O, ppm):
1.1-1.3 (4H), 1.5 (2H), 2.0
(4H), 2.3 (4H), 3.7 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 518 (m), 615 (m),
829 (m), 1033 (m), 1064 (m), 1170 (m), 1345 (m), 1400
(s), 1447 (m), 1634 (s), 2937 (m), 3234 (s), 3422 (s)

Example 22 ΔNP (OH) [Glt · Pt (CPA) ₂ ]
Synthesis of _0.9 (Glt · K ₂ ) _0.1 · 2H ₂ O｝ _n (CPA) ₂ PtI ₂ 1.98 g (3.52 mmol), Ag ₂
1.10 g (3.52 mmol) of SO ₄ and [NP (OH)
(Glt · K ₂ )] _n Example 1 (1.0 g, 3.52 mmol)
Reaction was carried out in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 24.1; H, 3.98; N, 9.10; P, 4.
97; Pt, 34.0 Theoretical value (%): C, 23.6; H, 4.50; N, 10.1; P, 5.
86; Pt, 33.2 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 0.7 (8H), 2.1-
2.4 (6H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 1124 (m), 1388
(s), 1631 (s), 3086 (s), 3184 (s)

Example 23 ｛NP (OH) [Glt · Pt (NH ₃ ) ₂ ] · 3H ₂
Synthesis of O｝ _n 1.70 g (3.52 mmol) of (NH ₃ ) ₂ PtI ₂ , Ag ₂
1.10 g (3.52 mmol) of SO ₄ and [NP (OH)
(Glt · K ₂ )] _n Example 1 (1.0 g, 3.52 mmol)
Reaction was carried out in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 12.0; H, 3.21; N, 10.1; P, 5.
83; Pt, 38.4 Theoretical value (%): C, 12.3; H, 3.88; N, 11.5; P, 6.
33; Pt, 39.9 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 2.2 (2H), 2.5 (2
H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 526 (m), 617 (m),
857 (m), 1111 (m), 1344 (m), 1386 (s), 1628 (s), 2960
(m), 3092 (s), 3250 (s), 3460 (s)

Example 24 ΔNP (OH) [Glt · Pt (THPDMA)]
Synthesis of _0.8 (Glt · K ₂ ) _0.2 · 2H ₂ O｝ _n (THPDMA) 2.09 g (3.52 mmol) of PtI ₂ ,
1.10 g (3.52 mmol) of Ag ₂ SO ₄ and [NP (O
H) (Glt · K ₂ )] _n (1.0 g, 3.52 mmol) was reacted in the same manner as in Example 21 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 23.8; H, 4.33; N, 10.7; P, 5.
45; Pt, 31.5 Theory (%): C, 24.1; H, 4.53; N, 9.53; P, 5.
85; Pt, 29.5 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.5 (4H), 2.4-
2.6 (8H), 3.7 (5H) Infrared spectrum (KBr cell, cm ^-1 ): 518 (m), 620 (m),
1116 (m), 1167 (m), 1384 (s), 1638 (s), 2945 (m), 3234
(s), 3446 (s)

Example 25 ΔNP (OH) [Glt · Pt (BAMPDO)]
Synthesis of _0.8 (Glt · K ₂ ) _0.2 · 2H ₂ O｝ _n (BAMPDO) PtI ₂ 2.05 g (3.52 mmol),
1.10 g (3.52 mmol) of Ag ₂ SO ₄ and [NP (O
H) (Glt · K ₂ )] _n (1.0 g, 3.52 mmol) was reacted in the same manner as in Example 21 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 22.4; H, 5.62; N, 11.6; P, 6.
12; Pt, 34.2 Theoretical (%): C, 22.3; H, 4.61; N, 10.4; P, 6.
38; Pt, 32.2 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 2.0-2.6 (12H),
3.6 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 526 (m), 1044 (m),
1228 (m), 1275 (m), 1384 (s), 1457 (m), 1618 (s), 2925
(m), 3202 (s), 3404 (s)

Example 26 ΔNP (OCH ₃ ) [Glt · Pt (DACH)]
_0.8 (Glt · K ₂ ) Synthesis of _0.2 · 2H ₂ O｝ _n 3.0 g of polydichlorophosphazene, L-glutamoyl dibenzyl ester-p-toluenesulfonate 13.
1.0 g of [NP (OCH ₃ ) (L-Glt · K ₂ )] _n obtained by reacting 6 g (27.2 mmol) and 50 ml of methanol.
(3.35 mmol) and 1.89 g of (DACH) PtI ₂
(3.35 mmol) and 1.04 g of Ag ₂ SO ₄ (3.35 m
mol) was reacted in the same manner as in Example 13 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 25.0; H, 4.66; N, 9.26; P, 5.
90; Pt, 29.4 Theoretical (%): C, 25.0; H, 4.70; N, 9.71; P, 5.
97; Pt, 30.1 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.1-1.3 (4H),
1.5 (2H), 2.1 (4H), 2.4 (4H), 3.3 (3H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 514 (m), 609 (m),
813 (m), 1052 (m), 1170 (m), 1213 (m), 1240 (m), 1387
(s), 1618 (s), 2940 (m), 3254 (s), 3420 (s)

Example 27 ｛NP (OCH ₃ ) [Glt · Pt (NH ₃ ) ₂ ]
Synthesis of _0.85 (Glt · K ₂ ) _0.15 · 2H ₂ O｝ _n 1.62 g (3.35 mmol) of (NH ₃ ) ₂ PtI ₂ , Ag ₂
1.04 g (3.69 mmol) of SO ₄ and [NP (OCH ₃ )
(Glt · K ₂ )] _n 1.0 g (3.35 mmol) in Example 2
Reaction was carried out in the same manner as in Example 6 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 15.8; H, 4.78; N, 10.6; P, 6.
36; Pt, 35.1 Theoretical (%): C, 15.7; H, 3.97; N, 11.3; P, 6.
73; Pt, 36.0 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 2.2 (2H), 2.5 (2
H), 3.4 (3H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 528 (m), 619 (m),
889 (m), 1112 (m), 1245 (m), 1337 (m), 1389 (s), 1621
(s), 2948 (m), 3241 (s), 3354 (s)

Example 28 ΔNP (OC ₂ H ₅ ) [Glt · Pt (DACH)]
_0.8 (Glt · K ₂ ) Synthesis of _0.2 · 2H ₂ O｝ _n 3.0 g of polydichlorophosphazene, L-glutamoyl dibenzyl ester-p-toluenesulfonate 13.
[NP (OCH ₂ CH ₃ ) (L-Glt · K ₂ )] _n obtained by reacting 6 g (27.2 mmol) and 50 ml of ethanol.
1.0 g (3.19 mmol) and (DACH) PtI ₂
80 g (3.19 mmol) and 0.99 g of Ag ₂ SO ₄ (3.
19 mmol) was reacted in the same manner as in Example 26 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 27.7; H, 5.42; N, 9.01; P, 5.
31; Pt, 29.4 theoretical (%): C, 26.5; H, 4.9
4; N, 9.44; P, 5.80; Pt,
29.2 Hydrogen nuclear magnetic resonance spectrum _(D 2 O, ppm):
1.1-1.3 (7H), 1.6 (2H), 2.0
(4H), 2.4 (4H), 3.4 (2H),
3.8 (1H) infrared spectrum (KBr cell, cm ^-1 ): 518 (m), 874 (m),
964 (m), 1033 (m), 1065 (m), 1124 (m), 1173 (m), 1245
(m), 1302 (m), 1387 (s), 2925 (m), 3234 (s), 3438 (s)

Example 29 ΔNP (NHCH ₃ ) [Glt · Pt (DACH)]
_0.8 (Glt · K ₂ ) Synthesis of _0.2 · 2H ₂ O｝ _n 3.0 g of polydichlorophosphazene, L-glutamoyl dibenzyl ester-p-toluenesulfonate 13.
6 g (27.2 mmol) and methylamine (54.4 mmol)
[NP (NHCH ₃ ) (L-Glt · K
₂ )] _n 1.0 g (3.36 mmol) and (DACH) PtI
₂ 1.89 g (3.36 mmol) and Ag ₂ SO ₄ 1.05 g
(3.36 mmol) was reacted in the same manner as in Example 18 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 25.3; H, 5.53; N, 12.0; P, 5.
76; Pt, 30.1 Theoretical (%): C, 25.0; H, 4.90; N, 12.4; P, 5.
98; Pt, 30.1 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.1-1.3 (4H),
1.6 (2H), 2.0 (2H), 2.5 (5H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 518 (m), 614 (m),
904 (m), 1060 (m), 1082 (m), 1201 (m), 1248 (m), 1307
(m), 1403 (s), 2938 (m), 3194 (s), 3418 (s)

Example 30 ΔNP (N (CH ₃ ) ₂ ) [Glt · Pt (DAC
H)] _0.8 (Glt · K ₂ ) _0.2 · 2H ₂ O｝ _n Synthesis of 3.0 g of polydichlorophosphazene, L-glutamoyl dibenzyl ester-p-toluenesulfonate 13.
6 g (27.2 mmol) and 2.22 g (27.2 mmol) of dimethylamine hydrochloride were reacted to obtain [NP
(N (CH ₃ ) ₂ ) (L-Glt · K ₂ )] _n 1.0 g (3.2
1 mmol) and 1.81 g (3.21 g) of (DACH) PtI _2.
mmol) and 1.0 g (3.21 mmol) of Ag ₂ SO ₄ were reacted in the same manner as in Example 29 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 27.4; H, 5.80; N, 11.8; P, 5.
12; Pt, 29.0 Theoretical (%): C, 26.6; H, 5.15; N, 12.1; P, 5.
82; Pt, 29.3 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.1-1.3 (4H),
1.6 (2H), 2.0 (4H), 2.4-2.6 (10H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 510 (m), 625 (m),
980 (m), 1056 (m), 1151 (m), 1162 (m), 1240 (m), 1293
(m), 1397 (s), 1628 (s), 2923 (m), 3198 (s), 3432 (s)

Example 31 ΔNP (OH) [Am · Pt (DACH)]
Synthesis of _0.9 (Am · Na ₂ ) _0.1 · 2H ₂ O｝ _n 3.0 g of polydichlorophosphazene, 5.76 g (27.2 mmol) of diethylaminomalonate hydrochloride and 0.49 ml (27.2 mmol) of H ₂ O were reacted. [NP (OH) (Am.Na ₂ )] _n 1.0 g (4.44 mm)
ol) and 2.50 g (4.44 mmol) of (DACH) PtI ₂
l) and 1.38 g (4.44 mmol) of Ag ₂ SO ₄ were reacted in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 19.4; H, 4.01; N, 9.82; P, 5.
88; Pt, 34.5 Theoretical value (%): C, 20.3; H, 3.91; N, 10.7; P, 6.
23; Pt, 35.3 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.1-1.3 (4H),
1.5 (2H), 2.0 (2H), 2.3 (2H), 3.9 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 503 (m), 775 (m),
931 (m), 1034 (m), 1108 (m), 1173 (m), 1243 (m), 1342
(s), 1453 (m), 1641 (s), 2923 (m), 3208 (s), 3414 (s)

Example 32 ΔNP (OH) [Am · Pt (CPA) ₂ ]
Synthesis of _0.9 (Am · Na ₂ ) _0.1 · 2H ₂ O｝ _n (CPA) ₂ PtI ₂ 2.50 g (4.44 mmol), Ag ₂
1.38 g (4.44 mmol) of SO ₄ and [NP (OH)
(Am · Na ₂ )] Example 3 was 1.0 g (4.44 mmol) of _n.
Reaction was carried out in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 20.8; H, 4.31; N, 10.2; P, 6.
23; Pt, 33.9 Theoretical value (%): C, 20.3; H, 3.97; N, 10.7; P, 6.
23; Pt, 35.3 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 0.8 (8H), 2.3 (2
H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 534 (m), 754 (m),
931 (m), 1043 (m), 1182 (m), 1210 (m), 1394 (s), 1654
(s), 2915 (m), 3212 (s), 3429 (s)

Example 33 ΔNP (OH) [Am · Pt (NH ₃ ) ₂ ] · 2H ₂
Synthesis of O｝ _n (NH ₃ ) ₂ PtI ₂ 2.14 g (4.44 mmol), Ag ₂
1.38 g (4.44 mmol) of SO ₄ and [NP (OH)
(Am · Na ₂ )] Example 3 was 1.0 g (4.44 mmol) of _n.
Reaction was carried out in the same manner as in Example 1 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 8.81; H, 3.31; N, 11.9; P, 7.
57; Pt, 43.1 Theoretical (%): C, 8.63; H, 2.96; N, 12.6; P, 6.
99; Pt, 44.0 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ): 518 (m), 619 (m),
976 (m), 1072 (m), 1176 (m), 1334 (m), 1386 (s), 1632
(s), 2923 (m), 3219 (s), 3415 (s)

Example 34 ΔNP (OCH ₃ ) [Am · Pt (DACH)]
Synthesis of _0.8 (Am · Na ₂ ) _0.2 · 2H ₂ O｝ _n 3.0 g of polydichlorophosphazene, 5.76 g (27.2 mmol) of diethylaminomalonate hydrochloride and 50 ml of methanol were reacted to obtain NP (OCH ₃ )
(Am · Na ₂ )] _n (1.0 g, 4.18 mmol) and (DA
CH) PtI ₂ 2.35 g (4.18 mmol) and Ag ₂ S
1.30 g (4.18 mmol) of O ₄ was reacted in the same manner as in Example 13 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 21.5; H, 4.31; N, 9.72; P, 5.
90; Pt, 31.6 Theoretical value (%): C, 21.8; H, 4.20; N, 10.4; P, 6.
39; Pt, 32.2 hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm):
1.1-1.3 (4H), 1.5 (2H), 2.0
(2H), 2.3 (2H), 3.4 (3H),
3.8 (1H) infrared spectrum (KBr cell, cm ^-1 ):
507 (m), 775 (m), 931 (m),
1071 (m), 1033 (m), 1162
(M), 1248 (m), 1323 (s), 16
51 (s), 2930 (m), 3202 (s),
3428 (s)

Example 35 ΔNP (OCH ₃ ) [Am · Pt (NH ₃ ) ₂ ]
Synthesis of _0.85 (Am · Na ₂ ) _0.15 · 2H ₂ O｝ _n (NH ₃ ) ₂ PtI ₂ 2.02 g (4.18 mmol), Ag ₂
1.30 g (4.18 mmol) of SO ₄ and [NP (OCH ₃ )
(Am.Na ₂ )] Example 2 was prepared using 1.0 g (4.18 mmol) of _n.
Reaction was carried out in the same manner as in Example 6 to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 12.0; H, 3.81; N, 11.5; P, 6.
69; Pt, 37.9 theoretical (%): C, 11.2; H, 3.33; N, 12.1; P, 7.
25; Pt, 38.8 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 3.3 (3H), 3.8 (1
H) Infrared spectrum (KBr cell, cm ^-1 ): 507 (m), 614 (m),
714 (m), 920 (m), 1032 (m), 1074 (m), 1186 (m), 1234
(m), 1387 (s), 1443 (m), 1636 (s), 2932 (m), 3251 (s),
3421 (s)

Example 36 ΔNP (NHCH ₃ ) [Am · Pt (DACH)]
Synthesis of _0.8 (Am · Na ₂ ) _0.2 · 2H ₂ O｝ _n 3.0 g of polydichlorophosphazene, 5.76 g (27.2 mmol) of diethylaminomalonate hydrochloride and 54.4 mmol of methylamine were obtained by reacting [NP (N
HCH ₃ ) (Am · Na ₂ )] _n 1.0 g (4.20 mmol)
And 2.36 g (4.20 mmol) of (DACH) PtI _{2 and} 1.31 g (4.20 mmol) of Ag ₂ SO _{4 in} Example 18.
The reaction was carried out in the same manner as in the above to obtain a polymer platinum complex compound.

Elemental analysis (%): C, 23.1; H, 4.31; N, 12.6; P, 5.
83; Pt, 31.9 Theoretical value (%): C, 21.8; H, 4.42; N, 13.3; P, 6.
40; Pt, 32.3 Hydrogen nuclear magnetic resonance spectrum (D ₂ O, ppm): 1.1-1.3 (4H),
1.5 (2H), 2.0 (2H), 2.3 (2H), 2.6 (3H), 3.8 (1H) Infrared spectrum (KBr cell, cm ^-1 ):
518 (m), 609 (m), 765 (m),
1119 (m), 1259 (m), 1318
(M), 1323 (s), 1447 (m), 16
61 (m), 2912 (m), 3224 (s),
3396 (s)

[Anti-Cancer Activity Test] The anti-cancer activity test for the polymer platinum complex compound of the present invention was carried out by a standard method (Gold
In et al., Europ. J. Cancer, 17, 129 (1981)). 6-8 week old experimental mice (BDF
(1 mouse) 8 animals in one group, 10 ⁶
Each mouse leukemia cell L1210 was transplanted. The platinum complex compound of the present invention is dissolved in 0.9% physiological saline, and if necessary, 30 to 60 mg / kg is administered by intraperitoneal injection (ip) on the first, fifth and ninth days. Time (IL
S: Increased Life Span,%) and the number of surviving animals after 60 days were examined. Existing cisplatin was used as a control compound.

Table 1 shows the results. It can be seen that the anticancer activity of the polymer platinum complex of the present invention is extremely superior to cisplatin and carboplatin.

Also, regarding acute toxicity, the LD ₅₀ (160 mg / k) of the compound of Example 1 which is a representative compound of the present invention was used.
g) and the LD ₅₀ of the compound of Example 21 (130 mg / kg)
Much larger than the LD _{50 of} cisplatin (13 mg / kg)
It is similar to the LD _{50 of} carboplatin (180 mg / kg), indicating that the possibility of development as a third generation anticancer drug is very high.

[0098]

[Table 1]

Continuing on the front page (72) Inventor Zhao Ryohe 1110 Sangye 1-dong, Sowon-gu, Seoul, Republic of Korea 10310 Reopening of Sangye Apartment 103-1105 Mondong 56 Sanmasu apartment 105-706 (56) References JP-A-56-30430 (JP, A) JP-A-53-115691 (JP, A) US Patent 3,893,980 (US, A) US Patent 5,104,947 (US, A) ) WO 97/12891 (WO, A) BULL. KOREAN CHEM. SOC. , 16 ~ 11! (1995) P. 1074-1079 (58) Fields investigated (Int. Cl. ⁶ , DB name) C08G 79/02-79/06 A61K 31/80 C07F 15/00 CA (STN) REGISTRY (STN)

Claims (11)

(57) [Claims] 1. A high-molecular platinum complex compound represented by the following general formula (I). Embedded image Wherein the polymer skeleton is based on a polyphosphazene having P = N repeating units, and S is a group that imparts solubility, and is a hydroxyl group,
A represents an alkoxy group or an alkylamino group; A represents a monodentate neutral ligand, ammonia, or an alkylamine or cyclopropylamine (CPA) having 1 to 3 carbon atoms, or ethylenediamine (en), propylene Diamine (pn), 2-hydroxy-1,3-diaminopropane (HDAP), 2,2
-Dimethyl-1,3-diaminopropane (DMDA
P), 1,1-diaminomethylcyclobutane (DAMC
B), tetrahydro-4H-pyran-4,4-dimethanamine (THPDMA), 2,2-bisaminomethyl-
Two amines selected from 1,3-propanediol (BAMPDO) and trans-1,2-diaminocyclohexane (DACH) are combined to form an AA type chelating amine; x is an integer 0 Represents 1 or 2, the anionic portion of the aminodicarboxylic acid, depending on the type of aminodicarboxylic acid,
When x = 0, aminomalonic acid (Am) derivative, x = 1
Represents an aspartic acid (Asp) derivative, x = 2 represents a glutamic acid (Glt) derivative; M represents two alkali metal ions or two ammonium ions, or one alkaline earth ion M value indicating the content of the platinum complex is 0.2 to 1,
The n value indicating the degree of polymerization of polyphosphazene is 10 to 1
00. ] 2. The polymer platinum complex compound according to claim 1, wherein the m value is 1. 3. An ammonium salt or an alkali salt of the general formula (II) obtained by introducing into a polydichlorophosphazene an aminodicarboxylic acid derivative as a platinum complex compound linking agent and a group imparting solubility, and then subjecting the compound to a hydrolysis step. A metal salt or an alkaline earth metal salt of the general formula (III)
The polymer platinum complex compound of the general formula (I) according to claim 1, characterized in that it is reacted with an acidic salt of diamine platinum of V) at a molar ratio of 1: 0.2 to 1 in an aqueous solution at room temperature. Manufacturing method. Embedded image [Wherein, S, A, x, M, m and n are as defined above, M (I) represents an ammonium ion or an alkali metal ion, and M (II) represents an alkaline earth X ₂ represents an anion and represents 2
Number of NO ₃ ^- shows ion, or one SO ₄ ^2-ions. ] 4. The alkali metal salt of the general formula (II) or the alkaline earth metal salt of the general formula (III) is reacted with the diamine platinum acid salt of the general formula (IV) in a molar ratio of 1: 1. A method for producing the polymer platinum complex compound according to claim 3. 5. The aminodicarboxylic acid derivative is selected from aminomalonic acid, aspartic acid and glutamic acid methyl ester, ethyl ester, benzyl ester and alkylamide; and the group imparting solubility is a hydroxyl group, methoxy, ethoxy, The method for producing a polymer platinum complex compound according to claim 3, wherein the compound is an alkoxy group selected from (2) and (2-methoxy) ethoxy, or a water-soluble alkylamino group selected from methylamino and dimethylamino. 6. The alkali metal is sodium or potassium, the alkaline earth metal is barium or calcium, and the diamine platinum acid salt of the general formula (IV) is diamine platinum sulfate or diamine platinum nitrate. A method for producing the polymer platinum complex compound according to claim 3. 7. An alkali metal salt of the general formula (II) and a diamineplatinum (II) sulfate of the general formula (IV) are reacted at a molar ratio of 1: 0.2 to 1 in an aqueous solution at room temperature. The method for producing a polymer platinum complex compound according to claim 6, wherein the organic solvent is added after concentrating the reaction mixture. 8. The method according to claim 7, wherein the organic solvent is a single solvent selected from acetone, ethanol, methanol, and ethyl ether, or two or more solvents. 9. An alkali metal salt of the general formula (II) and a diamineplatinum (II) nitrate of the general formula (IV) are reacted in an aqueous solution at room temperature in a molar ratio of 1: 0.2 to 1; 7. Dialysis using a semipermeable membrane (passing a molecular weight of 1,000 or less).
3. The method for producing a polymer platinum complex compound according to item 1. 10. A barium sulfate of the formula (III) is reacted with a diamineplatinum (II) nitrate of the formula (IV) in an aqueous solution at room temperature in a molar ratio of 1: 0.2 to 1; 7. The method for producing a polymer platinum complex compound according to claim 6, wherein the compound is removed as a precipitate. 11. An anticancer agent comprising the polymer platinum complex compound of the general formula (I) according to claim 1 or 2 as an active ingredient.